In 2016, the World Health Organization adopted a Global Strategy and Action Plan on Ageing and Health to prioritize and recognize the needs of rapidly aging populations worldwide. Alzheimers disease (AD) is one of the most significant disease indications associated with aging. Characterized by the progressive decline of cognition, memory, thinking, language and learning ability, the risk of AD is substantially increased in individuals aged 65 or above. However, the development of AD has been postulated to occur over several decades. AD pathologies include enhanced levels of amyloid and tau protein in the cerebrospinal fluid (CSF) as well as the formation of senile plaques and neurofibrillary tangles that ultimately contribute to inflammation followed by neuronal death. In spite of many years of research, successful treatment strategies have not yet been identified 1, urging researchers and healthcare providers to develop and test novel approaches against AD. The use of lifestyle factors such as nutrition to mitigate age-related cognitive impairment has shown promise in observational studies 2. In prospective cohort studies, diets rich in fruits and vegetables are associated with reduced risk of AD 3 and lower cognitive decline 4. In particular, the Mediterranean diet (MeDi) that is rich in vegetables, fruits, whole grains, nuts and legumes show protective associations against neurodegeneration 5. In cognitively intact elderly, lower MeDi adherence was associated with increased AD markers such as brain pathology, atrophy and glucose hypometabolism compared to those with higher adherence 6. Interestingly, in another study no correlation was found between adherence to MeDi and -amyloid deposition in a cohort of healthy women 7. Clinical trials employing MeDi against AD are limited but currently there are 8 in the pipeline Clinicaltrials.gov. Conversely, consumption of Western-style diets (WeDi), comprising of large amounts of refined carbohydrates, red/processed meat and high-fat dairy, have been associated with poor outcomes related to AD 8. Although the association between diet and risk of AD are apparent from such studies, the lack of extrapolation of these observations into precise and actionable nutritional regimen development against AD has made such findings clinically futile 9. At the molecular level, plant components of the MeDi can alter the gut microbiome, reduce inflammation and enhance cellular stress response pathways 10. It is also likely that MeDi can act as a rich source of riboflavins, that are precursors to the electron carriers flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN). However specific molecular targets that can be modulated by MeDi have not been identified do date posing a challenge to comprehensively utilizing MeDi as an AD prevention tool. Thus, we propose to study the preventive role of MeDi in AD using the 5XFAD mice, where animals overexpress mutant human Amyloid Precursor Protein (App1) and Presenilin 1 (Psen1). Our hypothesis is that mice on MeDi would show better AD outcomes compared to mice on standard diet (StDi) and WeDi. We plan on quantitating these changes using diverse methodologies through the following specific aims. STUDY GOALS, DESIGN AND EXPECTED OUTCOMES: Aim 1: Determine whether MeDi prevents and WeDi exacerbates AD-related outcomes compared to StDi. Aim 2: Evaluate whether genetic manipulation of cytoprotection can alter AD-related outcomes in 5XFAD mice. 1. Sacks, C.A., J. Avorn, and A.S. Kesselheim, The Failure of Solanezumab - How the FDA Saved Taxpayers Billions. N Engl J Med, 2017. 376(18): p. 1706-1708. 2. Scarmeas, N., C.A. Anastasiou, and M. Yannakoulia, Nutrition and prevention of cognitive impairment. Lancet Neurol, 2018. 3. Gu, Y., et al., Mediterranean diet, inflammatory and metabolic biomarkers, and risk of Alzheimer's disease. J Alzheimers Dis, 2010. 22(2): p. 483-92. 4. Kang, J.H., A. Ascherio, and F. Grodstein, Fruit and vegetable consumption and cognitive decline in aging women. Ann Neurol, 2005. 57(5): p. 713-20. 5. Gardener, H. and M.R. Caunca, Mediterranean Diet in Preventing Neurodegenerative Diseases. Curr Nutr Rep, 2018. 7(1): p. 10-20. 6. Berti, V., et al., Mediterranean diet and 3-year Alzheimer brain biomarker changes in middle-aged adults. Neurology, 2018. 90(20): p. e1789-e1798. 7. Hill, E., et al., Adherence to the Mediterranean Diet Is not Related to Beta-Amyloid Deposition: Data from the Women's Healthy Ageing Project. J Prev Alzheimers Dis, 2018. 5(2): p. 137-141. 8. Nicolia, V., M. Lucarelli, and A. Fuso, Environment, epigenetics and neurodegeneration: Focus on nutrition in Alzheimer's disease. Exp Gerontol, 2015. 68: p. 8-12. 9. Thambisetty, M., Understanding mechanisms and seeking cures for Alzheimer's disease: why we must be extraordinarily diverse. Am J Physiol Cell Physiol, 2017. 313(4): p. C353-C361. 10. Martucci, M., et al., Mediterranean diet and inflammaging within the hormesis paradigm. Nutr Rev, 2017. 75(6): p. 442-455.